Project Summary ? Gastrointestinal Core The Gastrointestinal Core will provide the resources and innovative expertise to evaluate the bi-directional interaction between the gastrointestinal tract and central effects of drugs of abuse. The major impetus for this new core stems from the growing need for the evaluation of new compounds and pharmacological approaches to treat pain that are devoid of side-effects, particularly those associated with the gastrointestinal tract. Recent evidence that alterations in the gut microbiome affects several aspects of CNS functions, including those related to drug-induced anxiety and mood, suggests that understanding gastrointestinal effects for drugs of abuse is important and necessary. In particular, opioid-mediated gastrointestinal dysfunction represents a major effect that significantly limits their use for pain relief. Additionally, the complement of neurotransmitters, receptors and ion channels within the enteric nervous system are similar to those in the central neurons, and thus the gut also provides a useful model to examine the functional effects of drugs of abuse. Recent studies have further established that the gut-brain axis is bidirectional in which alterations of gut physiology can modulate central effects of drugs of abuse. The specific aims of the GI Core are to a) provide the resources to evaluate the effects of drugs of abuse on GI function, including in vivo and in vitro assays, and b) to evaluate the role of the microbiome on the central/peripheral effects of drugs of abuse. We will also utilize our recently developed methodologies to isolate and record from identified enteric neurons from transgenic mice and extrinsic sensory neurons from the dorsal root ganglia, to evaluate the mechanisms by which drugs of abuse affect ionic conductances and determine the role of the microbiome in the behavioral effects of drugs of abuse. Over the last decade, NIDA-funded investigators at VCU have recognized the need to evaluate various drugs of abuse in the gastrointestinal tract. Through collaboration with the Akbarali laboratory, their research has been expanded to investigate opioid sparing effects of endocannabinoids, mu receptor biased ligands, the effects of nicotinic agonists in reversal of opioid-induced constipation, and the interaction of HIV-1 Tat and morphine in enteric neurons, as well as developed the hypothesis defining the role of the gut microbiome in the development of opioid tolerance. Thus, this core enables young and established investigators to delve into an important physiological system relevant to drug abuse and provides training in this emerging field for drug abuse research.